Following my internal medicine residency and first year of endocrine fellowship, my clinical and laboratory experience has been focused on Type I diabetes. The two parallel areas of my research experience have involved the early immune abnormalities in Type I diabetes, and the lymphocyte abnormalities in the BB rat, the animal model of Type I diabetes. Each of the two areas provides information which is useful in the other, because of the many similarities between these two disease. My present research plan will extend my studies in these areas. In the human, I will correlate DR gene methylation with the surface expression of Ia antigen in lymphocytes and lymphocyte cell lines from patients with new onset Type I diabetes. I will further define the role of the Ia+ T cell by starting T cell clones with these cells, and will identify their surface phenotype with flow cytometry. A screening program of first degree relatives of Type I diabetics will be initiated to find "pre-diabetics" with Ia+ T cells. I will continue to collect information on newly diagnosed diabetics so that correlation between immune parameters and clinical course can be established. In the BB rat, I will start breeding experiments designed to segregate the two diabetogenic genes identified thus far, and perform transplantation experiments to isolate the site of the lymphopenia lesion. Mouse H-2 cDNA will be used to probe the RTI locus of the BB, to investigate the diabetogenic gene linked to this locus. The environment for these wide ranging studies is excellent. Our laboratory located in the Joslin Diabetes Center, offers research experience and facilities two floors away from a large, diverse clinical population. The research environment outside of the Joslin is also excellent; collaboration with researchers at Harvard Medical School and the Dana-Farber Cancer Institute will provide the support for my studies involving DR gene methylation and mouse H-2 cDNA.